Bis-chromonyl compounds



United States Patent 3,419,578 BIS-CHROMONYL COMPOUNDS Colin Fitzmauriceand Thomas Brian Lee, Holmes Chapel, England, assignors to FisonsPharmaceuticals Limited, Loughborough, England No Drawing. Filed Mar.22, 1966, Ser. No. 536,281 Claims priority, application Great Britain,Mar. 25, 1965, 12,626/65; Dec. 9, 1965, 52,414/ 65 32 Claims. (Cl.260--345.2)

ABSTRACT OF THE DISCLOSURE Bis-chromonyl compounds of the formula:

0 0 I I l 0+0 K H C OOH 02 0 o 2 R It R R and therapeutically acceptablesalts, esters and amides thereof, wherein R R R R R and R are the sameor different and each is H or halogen, lower alkyl, hydroxy, loweralkoxy, substituted lower alkyl or substituted lower alkoxy, and X is asaturated or unsaturated, substituted or unsubstituted, straight orbranched polymethylene chain which may be interrupted by one or morecarbocyclic rings or oxygen-containing heterocyclic rings, oxygen atomsor carbonyl groups, are useful as inhibitors of certain antigen-antibodyreactions, being particularly useful for the relief and prophylaxis ofasthma.

This invention is concerned with improvements in or relating to newchemical compounds and pharmaceutical compositions containing them.

It has now been found that certain new chromone derivatives, ashereinafter defined, possess special activity as inhibitors of theeffects of certain types of antigen-antibody reaction, as evidenced, forexample, by in vivo tests.

According to the invention, therefore, there are provided as newcompounds bis-chromonyl compounds of the formula:

I R1 R4 I I I I I H020 0/ 0/ 00211 11 R R6 R6 and functional derivativesthereof, in which R R R R R and R are the same or different and each isa hy drogen or halogen atom (e.g. a chlorine, bromine, iodine orfluorine atom), a lower alkyl (e.g. a methyl, ethyl, propyl, isopropyl,butyl or tertiaryl butyl group), hydroxy, lower alkoxy (e.g. a methoxy,ethoxy, propoxy, isopropoxy, butoxy or tertiary butoxy group) orsubstituted lower alkyl or lower alkoxy group, (for example ahydroxyloweralkoxy, loweralkoxyloweralkoxy, carboxyloweralkoxy,hydroxyloweralkyl or haloloweralkyl such as chro-, bromo-, iodoortfluoro-loweralkyl) and X is a saturated or unsaturated, substituted orunsubstituted, straight or branched polymethylene chain which may beinterrupted by one or more carbocyclic rings or oxygen containingheterocyclic rings, (e.g. benzene, dioxan, tetrahydrofuran, ordihydropyran rings), oxygen atoms or carbonyl groups.

In general, it is preferred that no more than one of R R and R and notmore than one of R R and R is other than hydrogen.

3,419,578 Patented Dec. 31, 1968 Accordingly a preferred embodiment ofthe invention is constituted by bis-chromonyl compounds of the formula:

0 o I R I OX0 I I H020 corn 0 o and functional derivatives thereof, inwhich R and R are the same or are different and each is a hydrogen orhalogen atom or an alkyl, hydroxy, alkoxy or substituted alkoxy group,and X has the meaning defined above.

Particularly preferred compounds according to the invention are'those inwhich all of R R R3, R R and R are hydrogen and accordingly a furtherpreferred embodiment of the invention is constituted by bis-chromonylcompounds of the formula:

I I I I 11010 0/ 0 002K and functional derivatives thereof, in which Xhas the meaning defined above.

The group X may be any of a wide variety of groups. Thus for example, itmay be a straight or branched saturated or unsaturated hydrocarbonchain. Further, X may be such a chain interrupted by one or more oxygenatoms, carbonyl groups or carbocyclic or heterocyclic rings and may besubstituted by one or more halogen atoms (e.g. chlorine, bromine, iodineor fluorine atoms), or hydroxy or lower alkoxy (e.g. methoxy, ethoxy,propoxy, isopropoxy, butoxy, tert.but0xy, etc.) groups. Specificexamples of the group X are groups of the formulae:

CH: 2H2

OH2CHOHCH2O CHzCHOHCHretc.

The group X is preferably a straight or branched hydrocarbon chain,which may be interrupted by one or more oxygen atoms, and contains from3 to 7 carbon atoms. Desirably such a chain is substituted by one ormore hydroxyl groups, a particularly preferred chain being the2-hydroxy-trimethylene chain (-CH CHOHCH The chain OX-O- may linkdifferent or corresponding positions on the chromone molecules.

A particularly preferred compound according to the COzH and itsfunctional derivatives.

Functional derivatives of the compounds according to the inventioninclude salts, esters and amides of one or more of the carboxylic acidfunctions present and esters of any hydroxylic functions present.

Salts of the bis-chromonyl compounds which may be mentioned are saltswith physiological acceptable cations, for example, ammonium salts,metal salts such as alkali metal salts (e.g. sodium, potassium andlithium salts) and alkaline earth metal salts (e.g. magnesium andcalcium salts) and salts with organic bases, e.g. amine salts such aspiperidine, triethanolamine and diethylaminoethylamine salts.

Esters which may be mentioned include simple alkyl esters (e.g. methyl,ethyl, propyl, isopropyl, butyl and tertiary butyl esters) and amideswhich may be mentioned include simple amides (for example amides withammonia and lower alkylamines such as methylamine, ethylalmine etc.) andmore complex amides with amino acids such as glycine.

The new bis-chromonyl compounds according to the invention have beenshown to inhibit the release and/ or action of toxic products whicharise from the combination of certain types of antibody and specificantigen, e.g. the combination of reaginic antibody with specificantigen. In man, it has been found that both subjective and objectivechanges which result from the inhalation of specific antigen bysensitised subjects are markedly inhibited by prior administration ofthe new bis-chromonyl compounds. Thus the new compounds are of greatvalue in the prophylactic treatment of extrinsic allergic asthma. It hasalso been found that the new bis-chromonyl compounds are of value in theprophylactic treatment of so-called intrinsic asthma (in which nosensitivity to extrinsic antigen can be demonstrated).

It has also been found that in certain virus/antibody neutralisationsystems the new bis-chrornonyl compounds enhance the neutralisingcapacity of the antiserum, and thus the new compounds may find use inthe treatment of viral infections.

According to a further feature of the invention, therefore, there isprovided a pharmaceutical composition comprising a bis-chromonylcompound according to the invention, preferably in the form of a salt,in association with a pharmaceutical carrier or diluent. There is alsoprovided a process for the manufacture of a pharmaceutical compositionwhich comprises mixing a bischromonyl compound with a carrier ordiluent.

The nature of the composition and the pharmaceutical carrier or diluentwill, of course, depend upon the desired route of administration, i.e.orally, parenterally or by inhalation.

The compositions according to the invention are especially useful forthe prophylactic treatment of asthma, i.e. the compositions areadministered to the patient at regular intervals (e.g. 4-6 hourly) inorder to inhibit the effects of asthmatic attacks from which the patientmay suffer. When employed in this manner, the dosage of composition ispreferably such that from 150 mg. of active compound are administered tothe patient at each administration.

In general, for the prophylactic treatment of asthma, the compositionswill be in a form suitable for administration by inhalation. Thus thecompositions may comprise a suspension or solution of the activeingredient in water for administration :by means of a conventionalnebulizer. Alternatively the compositions may comprise a suspension orsolution of the active ingredient in a conventional liquified propellantsuch as dichlorodifluoromethane or chlorotrifiuorethane to beadministered from a pressurised container. The compositions may alsocomprise the solid active ingredient diluted with a solid diluent, e.g.lactose, for administration from a powder inhalation device.

The pharmaceutical compositions according to the invention generallycontain a minor proportion of hischromonyl compound and a majorproportion of carrier or diluent. Thus, for example, the solutions foradministration by a conventional nebuliser will comprise a dilutesolution, e.g. about 0.5%, in sterile water, and compositions comprisingsuspensions or solutions in pressurised propellants will contain, forexample, about 2% of the active bis-chromonyl compound. However, wherethe composition comprises the solid bis-chromonyl compound diluted witha solid diluent, the diluent may be present in less, equal or greateramount than the solid active ingredient, for example the diluent may bepresent in an amount of from 50 to by weight of the solid activeingredient.

The invention also includes within its scope a method of inhibiting theeffects of the antigen-antibody reaction which comprises the priorapplication to the area of the antigen-antibody mechanism atherapeutically effective amount of a bis-chromonyl compound accordingto the invention.

According to a particular embodiment, the invention is for a method ofrelieving or preventing allergic airway obstruction which comprisesadministering to the patient a therapeutically effective amount (e.g.1-50 mg.) at suitable intervals, of a bis-chromonyl compound accordingto the invention, particularly in the form of a salt.

The new compounds according to the invention are prepared by linkingtogether two chromone-Z-carboxylic acids or precursors therefor.

According to a further feature of the invention, therefore, there isprovided a process for the preparation of bis-chromonyl compounds of theformula:

0 II R R l HH l HOG 2 O O COzH R R3 Rs 36 and functional derivativesthereof, in which R R R R, R and R have the meanings defined above,which comprises reacting in one or more stages,

(a) a compound of the formula:

Y R I (b) a compound of the formula:

and (c) a compound of the formula:

A-X'B in which Z is a hydroxy group and Y is a hydrogen atom, a groupCOCI-I or a group COOR (in which R is an alkyl group), or Y and Ztogether form a chain l --CO-CH=C-O or a chain i COCH2-OHO- (in which Wis a carboxylic acid group or a functional derivative thereof or a groupconvertible to a carboxylic acid group or a functional derivativethereof), Y and Z have the same definition as Y and Z above and may bethe same or different; and A and B are the same or different and each isa group capable of reacting with a hydroxyl group to form an etherlinkage, or one of A and B isa group capable of being converted to sucha reactive group; and X is such that the group A B-- (in which A and Bare the residues of A and B after the formation of ether linkages) hasthe same meaning as X; to form a compound of the formula:

and, if necessary, intermediately or subsequently converting Y and Zand/or Y and Z to chains of the formula -CO-CH=C(COOH)O, or functionalderivatives thereof.

As stated above, the process according to the invention may be carriedout in one or more stages. Thus, it may be carried out in two stages asfollows:

This procedure will generally be adopted when the two chromone moietiesof the desired bis-chromonyl compound are different, ie when R R and Rare difierent from R R and R In the two stage process, the groupings Yand Z or Y and Z may be modified at an intermediate stage but, ingeneral, it is not preferred to follow this route. When the two chromonemoieties of the desired bis-chromonyl compound are the same the reactionmay be carried out in two stages, or preferably, if Y and Z have thesame meanings as Y and Z, in one stage, i.e. by reaction of a compoundof the formula:

OH R

with a compound of the formula:

A--X'-B When the reaction is carried out in two stages the compoundAX--B may be such that one of A and B is a group capable of beingconverted to an ether linkage forming group. When both A and B are etherlinkage forming groups, the first stage of a two stage reaction will, ofcourse, be carried out using substantially equimolecular proportions ofthe two compounds.

Examples of groups A and B capable of reacting with a phenolic hydroxylgroup, such that an ether linkage is formed by X and the hydroxyl group,include halogen atoms, e.g. chlorine, bromine or iodine atoms, or otheranion forming groups such as tosylate or methane sulphonate groups.Where the group A contains a hydroxy group beta to the subsequentlyform-ed ether linkage the group A or B may represent an epoxide group,giving rise to a residue A or B of CH CHOH. The groups A and B may bethe same or different; thus a compound A--X-B capable of yielding aZ-hydroxy-trimethylene linkage is the compound:

Groups capable of being converted to reactive groups such that an etherlinkage may be subsequently formed include hydroxyl groups which may beconverted to halogen substituents or other anion forming groups such astosylate or methane sulphonate. The group A or B may alternatively be avinyl group (CH=CH which may subsequently be converted to an epoxide orhalohydrin group. Thus, an example of a compound AXB which may be usedto produce a Z-hydroxy-trimethylene linkage is allyl bromide.

The reaction between the chromone moiety or precursor therefor and thelinking compound A-X-B will be carried out under the conditions normallyemployed for the formation of ether linkages. Thus, the reaction willgenerally be carried out in the presence of aqueous alkali or a solventsuch as acetone or dioxan and at elevated temperature. Where the etherlinkage formation is carried out by reaction of the aromatic hydroxygroup and a compound AXB [in which A and/ or B is an anion forming group(e.g. halogen, methanesulphonate etc.) the reaction is desirably carriedout in the presence of an acid binding agent such as an alkali metalcarbonate (e.g. sodium carbonate or potassium carbonate) or an organicacid binding agent such as pyridine, diethylaniline or triethylamine.Where A and/ or B is an epoxide group the ether forming reaction may beconveniently carried out in the presence of a suitable catalyst, cg. inthe presence of a quaternary ammonium hydroxide.

The conversion, if necessary, of Y and Z and/ or Y and Z to the desiredchain -C0CH=C(COOH)O or functional derivative thereof will be carriedout simultaneously if Y and Z are the same as Y and Z and in separatestages if Y and Z are not the same as Y and Z. It is, however, generallypreferred that Y and Z are the same as Y and Z since this reduces thenumber of chemical stages involved.

In the following description of methods of converting Y and Z to thedesired chain or functional derivatives thereof reference will only bemade to one chromone moiety but it will, of course, be

understood that where Y and Z are the same as Y and Z the process willact simultaneously on both moieties.

A preferred process involves the conversion of the compound in which Yis a group COCH and Z is a hydroxy group (i.e. a substitutedo-hydroxyacetophenone) to a chain CO-CH C(COOR)O (in which R is ahydrogen atom or an alkyl group); i.e.

This reaction may be carried out by a number of routes. A preferredroute involves the reaction of the ohydroxyacetophenone with an oxalicacid derivative of the formula:

CORQ

HALO-R12 in which R is a halogen atom or a group OR' (in which R is analkyl group), R and R are both halogen atoms and R is a group OR or Rand R together represent an oxygen atom (=0) and R is a halogen atom ora group OR.

Thus a particularly preferred process involves reaction of theortho-hydroxy-acetophenone with a dialkyl oxalate, such as diethyloxalate, preferably in the presence of a condensation agent such as analkali metal alkoxide, e.g. sodium ethoxide, sodamide, metallic sodiumor sodium hydride and conveniently in the presence of an organic solventsuch as ether, dioxan, ethanol or benzene. This process goes through anintermediate of the formula:

where R is the alkyl group of the dialkyl oxalate, which intermediatemay be cyclised directly by heating or may be isolated and cyclised byheating in a suitable solvent in the presence of a cyclisation agentsuch as an acid. When the oxalic acid derivative is of the formula:

in which R" is an alkyl group, e.g. ethyl ethoxydichloroacetate, thereactants are desirably employed in substantially equimolecularproportions and the reaction is conveniently carried out in the presenceof a metallic catalyst such as finely divided metallic platinum,palladium or ruthenium. When the oxalic acid derivative is of theformula:

HalCO--COOR' e.g. ethyl oxalyl chloride, the reaction is convenientlycarried out in the presence of an acid binding agent. When the oxalatederivative is an oxalyl halide such as oxalyl chloride, the reaction issuitably carried out in the presence of an organic solvent and in thepresence of an acid binding agent.

The o-hydroxy-acetophenone may also be condensed with an ester ofglyoxalic acid to give a compound of the formula:

COCH

CILOOzR which may then be oxidatively cyclised to the desiredchromone-2-carboxylic acid. Non-oxidative cyclisation gives rise to thecorresponding chromanone which may be converted to the chromone asdescribed below.

A different route for the formation of the desired chromonyl compoundinvolves the conversion of Y and Z (when Y is COCH and Z is OH) to anintermediate of the formula:

in which V is a group convertible to a carboxylic acid, or functionalderivative thereof, and subsequent conversion of the group V to acarboxylic acid group or functional derivative thereof.

Examples of the group V are the nitrile group which mav be hydrolysed toa carboxylic acid group and groups such as methyl, hydroxymethyl,halomethyl (e.g. chloromethyl, bromoethyl, dichloromethyl,trichloromethyl), formyl, acetyl, vinyl and styryl groups, oxidisable orhydrolysable to a carboxylic acid rou The Z-methyl chromone may beprepared from the o-hydroxyacetophenone by condensation with an alkylacetate, in a similar manner to the condensation described above for thedialkyl oxalate,

The Z-methyl chromone also serves as an intermediate in the preparationof a number of other oxidisable derivatives. Thus, the 2-methyl chromonemay be converted into the corresponding 2-halomethyl-chromone, e.g., byreaction with hydrogen chloride and manganese dioxide in boiling aceticacid to produce a 2-chloromethyl chromone or by reaction with bromine inacetic acid to yield the 2-bromomethylchromone. The Z-halomethylchromone may be oxidised to the corresponding chromone-2-carboxylicacid, for example, with potassium permanganate, or may be hydrolysed,using, for example, moist silver oxide, to give the 2-hydroxymethylchromone which may then be oxidised to the chromone-2-carboxylic acid,for example, using chromium trioxide as oxidising agent in the presenceof acetic acid and at ambient temperature or below.

The 2-methyl chromone may further be reacted withp-nitrosodimethylaniline and the reaction product hydrolysed with dilutemineral acid to give the corresponding 2- formyl-chromone which may beoxidised to the corresponding chromone-Z-carboxylic acid using, forexample, chromium trioxide as reagent.

Condensation of the Z-methyl-chromone with a benzaldehydde in thepresence of a condensation catalyst gives the 2-styryl chromone whichmay be oxidised to the corresponding chromone-Z-carboxylic acid, forexample, using potassium permanganate.

A number of the chromone derivatives, other than the Z-methyl chormone,convertible to the chromone-Z-carboxylic acid may be prepared directlyfrom the o-hydroxy-acetophenone.

Thus, the Z-formyl chromone may be prepared by condensation of adialkoxy acetate of the formula:

(RO) .CHCOOR" which is subsequently cyclised either by direct heating orby heating in the presence of a cyclisation agent (Baker Venkataramanreaction).

The 2-vinyl chromone may likewise be prepared from theo-hydroxy-acetophenone by reaction with ethyl acrylate.

The compound in which Y is a hydrogen atom and Z is a hydroxyl group,i.e., the phenol of the formula;

may be converted to the corresponding chromone-Z-carboxylic acid by anumber of methods.

For example, the chromone-Z-carboxylic acid may be prepared by reactionof acetylene dicarboxylic acid or a dialkyl ester thereof, e.g., diethylacetylene dicarboxylate, with the phenol or with an alkali metal phenatethereof.

Where the acetylene dicarboxylic acid or ester thereof is reacted withthe alkali metal phenate, i.e., the compound of the formula:

in which M is an alkali metal atom, the reaction is desirably carriedout in the presence of an inert organic solvent or diluent to yield afumarate of the formula:

OC(CO OH)=CI-I-C 02B which is then, if necessary after hydrolysis,cyclised to the desired chromone-Z-carboxylic acid, for example byheating in the presence of a cyclisation catalyst such as sulphuricacid. In a modification of this process the acetylene dicarboxylic acidor ester thereof is replaced by a halo-fumaric acid or an ester thereof,e.g., diethyl chlorofumarate, or by a dihalosuccinic acid or esterthereof.

The chromone-Z-carboxylic acid may also be prepared from the phenol byreaction with a compound such as ethyl ethoxalylacetate.

In another method the phenol may be esterified, e.g.,

with ethyl ethoxalyl chloride to give an ester of the formula:

which may subsequently be cyclised in the presence of acetic acid or aderivative thereof (e.g. ethyl acetate or acetyl chloride) to give thedesired chromone-Z-carboxylic acid.

The phenol may alternatively be condensed with maleic anhydride to givea compound of the formula:

which may then be oxidatively cyclised to the desiredchromone-Z-carboxylic acid. Non-oxidative cyclisation gives rise to thecorresponding chromanone which may then be converted to the chromone asdescribed below.

The compound in which Z is a hydroxyl group and Y is a groupCOOR i.e.the substituted salicylic acid ester of the formula:

may be converted to the desired chromone-2-carboxylic acid by reactionwith a pyruvate ester of the formula:

if desired in the presence of a condensation agent such as an alkalimetal alkoxide (e.g. sodium ethoxide), sodamide, metallic sodium orsodium hydride, and preferably in the presence of an organic solventsuch as ethanol or dioxan.

When Y and Z together form a chain in which W is the desired carboxylicacid group or functional derivative thereof, obviously no modificationof Y and Z will be necessary. When W is group convertible to acarboxylic acid group, or a functional derivative thereof, it will havethe same meaning as: defined for V above and may be converted to thecorresponding carboxylic acid group as described for V above.

When Y and Z together form a chain i.e. a chromamone, the group W willremain unchanged or be converted to a carboxylic acid group as necessaryand further the chromamone will need to be dehydrogenated to thecorresponding chromone; which dehydrogenation may be carried out eitherbefore or after any conversion of W.

The dehydrogenation of the chromanone of the formula:

O R I OXO W 0 Ra R may, for example, be effected using selenium dioxideor other suitable dehydrogenating agents such as palladium black orchloranil.

Alternatively, dehydrogenation may be carried out by brominationfollowed by dehydrobromination. Thus, the chromanone may be brominatedusing N-bromosuccinimide in an inert solvent or by treatment withpyridinium perbromide in an inert solvent such as chloroform in thepresence of a free radical catalyst such as benzoyl peroxide, to yieldthe 3-bromo derivative which may be subsequently dehydrobrominated.

The processes described above generally lead to the formation of thechromone-2-carboxylic acids as such or in the form of their esters.These may be readily converted to other functional derivatives, e.g.salts or amides, by conventional methods.

The majority of the intermediates produced by the linkage of the twochromone moieties or precursors there:- for are in themselves new.

According to the invention, therefore, there are provided as newcompounds, compounds of the formula:

in which R R R R R R", X, Y, Z, Y and Z have the meanings defined above,provided that not more than one of Y and Z and Y and Z represents achain COCH=C(COOH)-O- or a functional derivative thereof and furtherprovided that when R R R R, R and R are hydrogen and Y and Y are groupsCOCH and Z and Z are hydroxyl groups, X is not a group CH CHOHCH linkingthe two positions para to the groups Y and Y.

This invention also provides a process for the preparation of the newintermediates which comprises reacting in one or more stages:

(a) a compound of the formula:

R2 33 (b) a compound of the formula:

Y! IL.

R R and (c) a compound of the formula:

( a) 1,3-bis 2-acetyl-3 -hydroxyphenoxy propane A mixture of 30.4 parts2,6-dihydroxyacetophenone, 20.2 parts of 1,3-dibromopropane and 12.8parts powdered potassium carbonate were heated under refiux in 200 partsby volume of acetone for 72 hours. The acetone solution was filtered andthe solid residue was washed first with acetone and then with water. Thecombined acetone filtrate and washings were evaporated leaving an oilwhich, on being boiled with ether, gave pale yellow crystals. These werecombined with the first obtained solid and extracted with refluxingisopropanol in a Soxhlet extractor for several days to obtain 16.1 partsof 1,3- bis(2-acetyl-3-hydroxyphenoxy)propane as almost colourlesscrystals melting between 184 and 185 C.

12 Arzalysis.-C H O requires: C, 66.2%; H, 5.81%. Found: C, 65.4%; H,5.68%.

(b) Diethyl ester of 1,3-bis(Z-carboxychromon-S- yloxy propane Asolution of 6.9 parts 1,3-bis(2-acetyl-3-hydroxyphenoxy) propane in 15parts by volume of diethyl oxalate was added to a solution of 3 partssodium in 30 parts by volume of ethanol and 50 parts by volume ofbenzene and the mixture was heated gently under reflux for 20 hours. Itwas then poured into a large volume of ether and the precipitated solidwas filtered, washed with ether and dried. It was then dissolved inwater and acidified to obtain a sticky solid. This was boiled with about50 parts of ethanol containing a catalytic amount of hydrochloric acidfor about 10 minutes, when crystals began to form. The solution wascooled and filtered to obtain 7.4 parts of solid melting between 178 and180 C. This was recrystallised from 200 parts by volume of a 1:2 mixtureof benzene and ethanol to obtain a first crop of 4.5 parts of thediethyl ester of 1,3 bis(2 carboxychromon-S- yloxy)propane, meltingbetween 182 and 183 C.

Analysis.C H O requires: C, H, Found: C, 63.2%; H, 4.60%.

(c) Dis'odium salt of 1,3-bis(Z-carboxychromon-S- yloxy propane Asuspension of 3 parts of the diethyl ester of 1,3-bis(2-carboxychromon-S-yloxy)propane in 50 parts by volume of boilingethanol was treated with 11.6 parts by volume of 1.015 N aqueous sodiumhydroxide. Water was added until a clear solution was obtained. This wastreated with charcoal, filtered and concentrated by boiling, with theoccasional addition of more ethanol. On cooling 2.2 parts of colourlesscrystals of the disodium salt of 1,3- bis(2 carboxychromon 5-yloxy)propane monohydrate were obtained.

Analysis.C H Na O H O requires: C, 53.7%; H, 3.11%. Found: C, 54.1%; H,2.86%.

EXAMPLE 2 (a) 1,3-bis(2-acetyl-3-hydroxyphenoxy)-2-hydroxypropane By themethod of Example 1(a) 10 parts of 2,6-dihydroxyacetophen'one, 4.6 partspotassium carbonate and 7.15 parts 1,3 dibromopropan 2 0] were reactedin acetone to obtain 3 parts of pure1,3-bis(2-acetyl-3-hydroxyphenoxy)-2-hydroxypropane as colourlesscrystals melting between 165 and 166 C.

Analysis.C H O- requires: C, 63.3%; H, 5.56%. Found: C, 63.5%; H, 5.86%.

(b) 1,3-bis(Z-acetyl-3-hydroxyphenoxy)-2- hydroxypropane To a solutionof 970 parts of 2, 6- dihydroxyacetophenone and 325 parts ofepichlorohydrin in 2,500 parts of hot isopropanol was added, withstirring under reflux, a solution of 233 parts of KOH in 2,500 parts ofisopropanol and sufficient water (ca. parts) to dissolve the solid. Themixture was heated, with stirring, under reflux for 48 hours. Half thesolvent was then disstilled off and 5000 parts of water were added. Themixture was cooled and the solid filtered off and washed withisopropanol and ether. It was then recrystallised from 12,500 parts ofisopropanol to obtain a first crop of 380 parts and a second crop, afterconcentration, of 300 parts of 1,3 bis(2 acetyl 3hydroxyphenoxy)-2-hydroxypropane identical with that obtained in Example2(a) above.

(0) Diethyl ester of 1,3-bis(Z-carboxychromon-S- yloxy)-2-hydroxypropaneBy the method of Example 1(b) 4.6 parts of 1,3-bis(2-acetyl-3-hydroxyphenoxy)-2hydroxypropane were reacted with diethyloxalate and the product cyclised to (d) Disodium salt of1,3-bis(2-carboxychromon-5- yloxy) -2-hydroxypropane By the method ofExample 1(0), 4 parts of the diethyl ester of 1,3bis(2-carb0xychromon-5-yloxy)-2-hydroxypropane were saponified to obtain3.2 parts of the disodium salt tetrahydrate as colourless crystals fromaqueous alcohol.

Analysis.C H Na O 4H O requires: C, 47.3%; H, 3.79%, Na, 7.7%. Found: C,47.8%; H, 3.8%; Na. 7.7%.

(a) 1,3-bis (Z-carboxychromon-S-yloxy)-2- hydroxypropane A solution ofthe disodium salt of 1,3-bis(2-carboxychromon-S-yloxy)-2-hydroxypropanein water was acidified and the precipitate was recrystallised fromethanol plus ether to obtain 1,3 bis(2 carboxychromon 5- yloxy) 2hydroxypropane monohydrate as colourless crystals melting withdecomposition between 216 and 217.

Analysis.C H O' H O requires: C, 56.8%; H, 3.70%. Found: C, 56.7%; H,3.44%.

Dehydration of the monohydrate in vacuo at 110 C. gave the anhydrousacid melting between 241 and 242 C. with decomposition.

(1?) Calcium salt of 1,3-bis(2-carboxychromon-5- yloxy)-2-hydroxypropaneThe disodium salt of 1,3 bis(2 carboxychromon-S- yloxy)-2-hydroxypropane (0.8 part) dissolved in the minimum volume of warmwater was treated with a solution of 0.225 part of calcium nitrate in asmall volume of water, to obtain the sparingly soluble calcium salt. Themixture was cooled and filtered, and the solid was washed with coldwater and dried at 110 C.

Analysis.--C H CaO 3H O requires: Ca, 7.14%. Found: Ca, 7.19%.

(g) Magnesium salt of 1,3-bis(2-carboxychromon-5- yloxy)-2-hydroxypr0pane A suspension of 2 parts of 1,3-bis(2-carboxychromon-S-yloxy)-2-hydroxypropane in 20 parts of water was treated with 0.36parts of magnesium carbonate. The mixture was boiled with stirring untilhomogeneous, cooled, filtered and dried at 110 C. to obtain 2.3 parts ofthe magnesium salt.

(h) Dipiperidine salt of 1,3-bis(2- carboxychromon-5- yloxy)-2-hydroxypropane A suspension of 2 parts of 1,3-bis(2-carboxychromon- 5yloxy) 2-hydroxypropane in 20 parts of water was treated with 0.7 partof piperidine. The mixture was warmed under reflux until a clearsolution was obtained after which it was cooled and dehydrated byfreeze-drying to obtain 2.8 parts of the dipiperidine salt of 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane.

Analysis.-C H NO .2H O requires: C, 59.1%; H, 5.67%; N, 4.18%. Found: C,59.0%; H, 6. 12%; N, 4.00%.

EXAMPLE 3 (a) 1,4-bis (2-acety1-3-hydroxyphenoxy)but-Z-ene By the methodof Example 1(a), 15.2 parts of 2,6- dihydroxy-acetophenone werecondensed with 10.7 parts of 1,4-dibrombut-. 2-ene to obtain 6 parts of1,4-bis(2- acetyl- 3-hydroxyphenoxy)but-2-ene melting between 145 and146 from acetone.

(b) 1,4bis(2-carboxychromon-5-yloxy)but-2-ene By the method of Example1*(b), 5 parts of 1,4-bis(2- acetyl-3-hydroxyphenoxy)but-Z-ene werecondensed with diethyl oxalate to obtain 3 parts of the diethyl ester of1,4-bis(2-carboxychromon-5-yloxy)but-2 ene as yellow crystals meltingbetween 215 and 217 C. from ethanol.

Analysis.C- H O requires: C, 64.6%; H, 4.6%. Found: C, 64.1%; H, 4.69%.

Saponification of 2 parts of the diethyl ester of 1,4-bis(Z-carboxychromon-S-yloxy)but-2-ene by the method of Example 1(c) gave1.5 parts of the disodium salt.

Acidification of an aqueous solution of this sodium salt gave the freeacid monohydrate, melting between 193 and 195 A nalysis.C H O H Orequires: 3.73%. Found: C, 59.6%; H, 3.56%.

EXAMPLE 4 1,12-bis(Z-carboxychromon-S-yloxy)-2,1l-dihydroxy-4,9-dioxadodecane A solution of 10 parts 2,6-dihydroxyacetophenone, 5.6parts butane-1,4-diol diglycidyl ether and 0.1 part of 40% aqueoussolution of benzyltrimethyla-mrnonium hydroxide in 14 parts diox-an washeated at 100 C. in a sealed vessel for 60 hours. The dioxan was removedunder reduced pressure leaving a thick yellow oil. This was extractedseveral times with boiling ether and the combined extracts werefractionally precipitated with petrol. The first fraction, which wasabout 5 parts of a clear yellow oil, could not be crystallised ordistilled but had an infra-red spectrum consistent with that expectedfor 1,12-bis(Z-acetyI-S-hydroxyphenoxy)-2,11-di'hydroxy-4,9dioxadodecane. This was condensed with diethyl oxalate by the method ofExample 1(b) to obtain 3 parts of the diethyl ester of 1,12-bis(2-carboxychromon-S-yloxy)-2,1l-dihydroxy 4,9 diox'adodecane as an oil.This oil was stirred and warmed with a saturated aqueous solution ofsodium bicarbonate until dissolved. The solution was filtered andacidified with dilute hydrochloric acid. The precipitate was dissolvedin ethanol plus ethyl acetate, treated with charcoal, filtered andprecipitated with petrol and the solid was recrystallised from acetoneplus ether to obtain 1 part of pure 1,12-bis(2-carboxychromon-S-yloxy)-2,11-dihydroxy 4,9 dioxadodeoane dihydrate ascolourless crystals melting with decomposition at C.

Analysis.C H O 2'H O requires: C, 55.3%; H, 5.22%. (Found: C, 55.3%; H,5.24%.

1,12-bis(2-carboxychromon-5-yloxy) 2,11 dihydroxy- 4,9-dioxadodecanedihydrate (0.325 part) was dissolved in a solution of 0.084 part sodiumbicarbonate in parts water. The solution was filtered and freeze-driedto obtain 0.3 part of the disodium salt tetrahydrate.

Analysis.C H Na O 4H O requires: C, 49.3%; H, 4.9%. Found: C, 48.7%; H,4.75%.

EXAMPLE 5 (a) 1,4-bis (2-acetyl-3 -hydroxyphenoxy) butane By the methodof Example 11(a) 2,6-dihydroxyacetophenone was reacted with1,4-dibromobutane to obtain 1,4-bis (2-acetyl-3-hydroxyphenoxy)butanemelting between 219 and 221 C. from benzene.

Analysis.C H O requires: C, 67.0%; H, 6.2%. Found: C, 66.0%; H, 6.0%.

(b) Diethyl ester of 1,4-bis(2 carboxychromon-5-yloxy) butane By themethod of Example 1(b) 1,4-bis(2-acetyl-3- hydroxyphenoxy)butane wascondensed with diethyl oxalate to form the diethyl ester of1,4-bis(2-carboxychromon-5-yloxy)butane melting between and 199 C. froma mixture of ethyl acetate and isopropanol.

AnaIysiS.-C H O H O requires: C, 62.3%; H, 5.2%. Found: C, 62.4%; H,5.1%.

(c) 1,4-bis 2-carboxychromon-5-ylox.y butane The diethyl ester of 1,4-bis(2-carboxychron1on-5-y1oxy) butane was hydrolysed by heating withaqueous sodium bicarbonate until dissolved, filtering and acidifying thesolution. The precipitate was recrystallised from methanol to obtainpure 1,4-bis(Z-oarboxychromon-S-yloxy)butane monohydrate melting between228 and 230 C.

Analysis.-C H O H O requires: C, 59.5% H, 4.2%. Found: C, 58.6%; H,3.95%.

This acid was dissolved in an equivalent amount of sodium bicarbonatesolution and freeze-dried to obtain the disodium salt.

EXAMPLE 6 1,5 -bis 2-carboxychromon-5 -yloxy pentane2,6-dihydroxyacetophenone was reacted with 1,5-dibrmopentane as inExample 1(a) to obtain l,5-bis(2-acetyl- 3-hydroxyphenoxy)pentanemelting between 131 and 133 C. from benzene.

Analysis.C H O requires: C, 67.7%; H, 6.5%. Found: C, 67.4%; H, 6.3%.

This diketone was condensed with diethyl oxalate as in Example 1(b) toobtain the diethyl ester of 1,5-bis(2- carboxychromon-S-yloxy)pentane,melting between 150 and 152 C. from ethanol.

Analysis.C H O requires: C, 64.8%; H, 5.3% Found: C, 64.6%; H, 5.3%.

The ester was hydrolysed as in Example 5(c) to obtain the acid as amonohydrate melting between 226 and 228 C. from ethanol.

Analysis.C H O H O requires: C, 60.2% H, 4.4%. Found: C, 60.3%; H, 4.7%.

The acid was subsequently converted to the disodium salt by the methodof Example 5 (c).

EXAMPLE 7 1,6-bis(2-carboxychromon-5-yloxy) hexane2,6-dihydroxyacetophenone was reacted with 1,6-dibromohexane as inExample 1(a) to obtain 1,6-bis(2- acetyl-3-hydroxyphenoxy) hexanemelting between 147.5 and 148.5 C. from ethanol.

AnaZysis.C H O requires: C, 68.4%; H, 6.8%. Found: C, 68.1%; H, 6.7%.

This diketone was condensed with diethyl oxalate by the method ofExample 1(b) to obtain the diethyl ester of 1,6-bis(2carboxychromon-5-yloxy)hexane melting between 154.4 and 155 C. fromethtanol.

Analysis.C H O requires: C, 65.4%; H, 5.5%. Found: C, 65.0%; H, 5.4%.

The ester was hydrolysed as in Example 5(c) to obtain the acidmonohydrate melting between 228 and 230 C. from dioxan.

Analysis.C H O H O requires: 4.7%. Found: C, 60.2%; H, 4.9%.

The disodium salt of the acid was subsequently prepared as in Example 5(c) EXAMPLE 8 1,10-bis(2-carboxychromon-5-yloxy)decane2,6-dihydroxyacetophenone was condensed with 1,10- dibromodecane as inExample 1(a) to obtain 1,10-bis (2-acetyl-3-hydoxyphenoxy) decanemelting between 102.5 and 104 C. from ethyl acetate.

Analysis.C H O requires: C, 70.6%; H, 7.7%.

Found: C, 70.0%; H, 7.4%.

This diketone was reacted with diethyl oxalate as in Example 1(b) toobtain the diethyl ester of 1,10-bis(2- carboxychromon-S-yloxy)decanemelting between 146.5 and 148 C. from ethanol plus dioxan.

Analysis.C H O requires: C, 67.3%; H, 6 .33%. Found: C, 67.4%; H, 6.45%.

The ester was hydrolysed by boiling with aqueous sodium bicarbonate toobtain the sparingly soluble disodium salt which was recrystallised fromwater.

Analysis.C H Na O requires: C, 60.6%; H, 4.7%. Found: C, 61.0%; H, 5.2%.

1 6 EXAMPLE 9 1,7-bis(2-rcarboxychromon-S-yloxy) -2,6-dihydroxy-4-oxa'heptane EXAMPLE 10 The ester was hydrolysed as in Example 5(c) toobtain 2,6-dihydroxyacetophenone was condensed with 2,2- dibromodiethylether, as in Example 1(a) to obtain 1,5-bis(2-acetyl-3-hydroxyphenoxy)-3-oxapentane melting between 120.5 and121.5 C. .from methanol.

Analysis.-C H O requires C, 64.1%; H, 5.9%. Found: C, 63.5%; H, 5.1%.

This was condensed with diethyl oxalate as in Example 1(b) to obtain thediethyl ester of 1,5-bis(2-'carboxychromon-S-yloxy)-3-0xapentane meltingbetween 129 and 13 1.5 C. from methanol.

Analysis.C H O requires: Found: C, 62.3%; H, 4.9%.

The ester was hydrolysed as in Example 5 (c) to obtain the acid meltingbetween 219 and 220 C. from ethanol plus dioxan.

Analysis.C H O requires: C, 59.8%; H, 3.8%. Found: C, 59.8%; H, 3.9%.

The disodium salt of the acid was subsequently prepared as in Example 5(c).

EXAMPLE 11 1,4-bis (Z-carboxychromon-5-yl0xy) -2, 3-dihydroxybutane2,6-dihydroxyacet0phenone was reacted with 1,2:3,4- bisepoxybutane as inExample 4 to obtain 1,4-bis(2-acety1-3-hydroxyphenoxy)-2,3-dihydroxybutane, melting between 211 and 212 C.from dioxan.

Analysis.C H O requires: C, 61.5%; H, 5.7%. Found: C, 61.0%; H, 5.7%.

This was condensed with diethyl oxalate as in Example 1(b) to obtain thediethyl ester of 1,4 bis(2-carboxychromon-S-yloxy)-2,3-dihydroxybutanemelting between 224 and 226 C.

Analysis.C H O requires: C, 60.6%; H, 4.7%. Found: C, 59.2%; H, 4.6%.

This was hydrolysed by the method of Example 5 (c) to obtain the acid asa dihydrate melting between 260 and 262 C.

Analysis.C H O 2H O requires: C, 54.0%; H, 4.1%. Found: C, 54.0%; H,3.7%.

This was subsequently converted to the disodium salt as in Example 5(c).

EXAMPLE 12 1,4-bis (Z-carboxychromon-5-yloxy) -2-hydroxybutane2,6-dihydroxyacetophenone was condensed with 1- bromo-3,4-epoxybutane byboiling in acetone in presence of potassium carbonate to obtain1,4-bis(2-acetyl-3-hydroxyphenoxy)-2-hydroxybutane melting between 207.5and 208.5 C. from methanol.

Analysis.C H O requires: C, 64.2%; H, 5.9%. Found: C, 63.4%; H, 5.8%.

This was condensed with diethyl oxalate as in Example l(b) to obtain thediethyl ester of 1,4-bis(2-carboxychromon-S-yloxy)-2-hydroxybutanemelting between 216 and 217 C. from a mixture of chloroform, ethylacetate and petrol.

Analysis.-C H O requires: C, 62.4%; H, 4.9%. Found: C, 62.7%; H, 5.2%.

This was hydrolysed as in Example 5 (c) to obtain the acid as amonohydrate melting between 226 and 227 C.

Analysis.-C H O H O requires: C, 57.6%; H, 4.0%. Found: C, 57.1%; H,3.9%.

This was subsequently converted to the disodium salt as in Example 5(c).

EXAMPLE 13 1, S-bis (2-carb oxychromon-7-yloxy pentane Ethyl7-hydroxychromone-2-carboxylate was condensed with one half equivalentof 1,5-dibromopentane by heating in acetone in presence of potassiumcarbonate to obtain the diethyl ester of 1,5 bis(2 carboxychromon 7-yloxy)pentane melting between 148 and 150 C. from ethanol.

Analysis.--C H O requires: C, 64.8%; H, 5.3%. Found: C, 64.6%; H, 5.3%.

This ester was hydrolysed as in Example 5(c) to obtain the acid meltingbetween 283 and 284 C.

Analysis.C H O requires: C, 62.4%; H, 4.2%. Found: C, 61. 8%; H, 4.2%.

The acid was subsequently converted to the disodium alt by the method ofExample 5(c).

EXAMPLE 14 1, IO-bis (2-carboxychromon-S-yloxy -3,-8-dioxa- 4,7-dioxodecane Ethyl 5-(2-hydroxyethoxy) chromone-Z-carboxylate (1.4parts) and 0.4 part succinyl chloride were dissolved in chloroform andtreated with 0.5 part pyridine. The mixture was heated under reflux for16 hours. The chloroform solution was washed with dilute hydrochloricacid, sodium carbonate solution and water and dried over sodiumsulphate. The chloroform was distilled to leave an oil which wassolidified by trituration with petrol. It was recrystallised fromethanol to obtain 0.2 part of the diethyl ester of 1,LObis(2-carboxychromon-5-yloxy)-3,8-dioxa- 4,7-dioxodecane melting between144 and 146 C.

Analysis.C H O requires: C, 60.2%; H, 4.69%. Found: C, 60.5%; H, 4.97%.

EXAMPLE 15 l,S-bis(2-carboxy-8-chlorochromon-5-yloxy)pentane A mixtureof 4.62 parts of 1,5-bis(2-acetyl-3-hydroxyphcnoxy) pentane (fromExample 6) and 2.7 parts of sulphuryl chloride in 300 parts of dry etherwas stirred for 7 hours at room temperature. The solution was [filteredand evaporated to dryness leaving a yellow solid. This wasrecrystallised from ether to obtain 2.36 parts of 1,5-bis(2aceytl-4-chloro-3-hydroxyphenoxy)pentane as pale yellow prisms meltingat 96 C.

.This was condensed with diethyl oxalate as in Example 1(b) to obtainthe diethyl ester of 1,5-bis(2-carboxy-8- chlorochromon-S-yloxy)pentanemelting between 162 and 164 C. from ethanol.

Analysis.C H Cl O requires: C, 57.5%; H, 4.3%. Found: C, 57.7%; H, 4.3%.

The ester was hydrolysed as in Example 5 (c) to obtain the acid, meltingat 244 C. from ethanol.

Analysis.C H Cl O requires: C, 54.7%; H, 3.28%; Cl, 12.9%. Found: C,54.2%; H, 4.6%; Cl, 12.9%.

The acid was converted to the disodium salt by the method of Example5(0).

EXAMPLE 16 (a) 2-(2,3-epoxypropoxy)-6-hydroxyacetophenone To a mixtureof 5.68 parts of 2,6-dihydroxyacetophenone, 10.3 parts ofepichlorohydrin and 3 parts (by volume) of ethanol which was stirred andgently refluxed, was added slowly a solution of 2.58 parts of potassiumhydroxide in 7 parts (by volume) of ethanol and 1 part (by volume) ofwater. The mixture was then stirred and refluxed for 1 hour, then aftercooling an excess of water was added and the product was extracted intoether and the solution was dried over sodium sulphate. After removingthe drying agent and the solvent 5 parts of a crude oil remained. Thisoil was extracted using; hot petrol ether (B.P. 40-60) and on coolingyellow crystals of 2-(2,3- epoxypropoxy)-6-hydroxyacetophenone M.P.61-63 separated.

Analysis.C H O requires: C, 63.45%; H, 5.8%. Found: C, 63.5%; H, 5.7%.

(b) 1- 2-acetyl-3-hydroxyphenoxy) -3- (4-acetyl-3- hydroxyphenoxy-2-hydroxyp rop ane A mixture of 5 parts of-2'(2,3-epoxypropoxy)-6-hydroxyacetophenone, 3.8 parts ofresacetophenone, 20 parts (by volume) of dioxan and 5 drops of trimethylbenzyl ammonium hydroxide solution were heated at C. in a sealed bottleovernight. After cooling the product crystallised out and wasrecrystallised from dioxan to yield 2 parts ofl-(2-acetyl-3hydroyphenoxy)-3-(4-acetyl-3-hydroxyphenoxy)-2-hydroxypropanemelting between 182 and C.

Analysis.-C H O requires: C, 63.3%; H, 5.6%. Found: C, 62.8%; H, 5.4%.

(c) 2- 3-chloro-2-hydroxypropoxy) -6-hydr0xyacetophenone A mixture of 10parts of 2,G-dihydroxyacetophenone, 7 parts of epichlorohydrin in 18parts (by volume) of dioxan and 5 drops of Triton B, was heated at 100C. in a sealed vessel for 2 /2 days. The solvent was then removed underreduced pressure and an excess of ether was added to the residue. Theether solution was decanted from the insoluble, washed with water (2 50parts) and 2 N sodium carbonate (3 X 25 parts). The solvent was removedafter drying over sodium sulphate and the residue was purified bychromatography using an alumina column and ether as eluent. The oil wasdistilled to obtain 2-(3- chloro-Z-hydroxypropoxy) 6 hydroxyacetophenone(6 parts) as a yellow oil B.P. 166-8 at 1.5 mm.

Analysis.C H ClO requires: C, 54.0%; H, 5.32%. Found: C, 53.7%; H,5.26%.

(d) 1-(2'acetyl-3-hydroxyphenoxy)-3-(4acetyl-3-hydroxyphenoxy) -2-hydroxyp ropane To the above chlorohydrin (6 parts) was added 3.8 parts ofresacetophenone, 3.5 parts of anhydrous potassium carbonate and 50 parts(by volume) of dry acetone. This mixture was refluxed for 2 days. Thenthe insoluble material was filtered, after cooling, and stirred in waterto remove inorganic material. Recrystallisation of the residue fromdioxan yielded 0.7 part of1-(2-acetyl-3-hydroxyphenoxy)3-(4-acetyl-3-hydroxyphenoxy) 2hydroxypropane melting between 182 and 185 C. and identical with theproduct from (b) above. From the acetone filtrate a further 2 parts ofthis product were obtained.

(e) 1 (2 ethoxycarbonylchromon 5' yloxy) 3-(2-ethoxycarbonylchromon-7-yloxy)-2-hydroxypropane By the method of Example1( b) l-(2-acetyl-3-hydroxyphenoxy) 3 (4acetyl-3-hydroxyphenoxy)-2-hydroxyprop-ane was condensed with diethyloxalate to form 1-(2- ethoxycarbonylchromon-5-yloxy)-3-(2ethoxycarbonylchromon-7-yloxy)-2-hydroxypropane melting between 193 and194.5 C. from ethanol plus dioxan.

Analysis.-C H O requires: C, 61.8%; H, 4.6%. Found: C, 62.0%; H, 4.3%.

(f) 1-(2-carboxychromon-5-yloxy) -3-(2-carboxychromon-7-yloxy-2-hydroxyprop ane The ester from (e) above was hydrolysed as in Ex-EXAMPLE 17 (a) 1-(2-acetyl-3-hydroxyphenoxy)--(4-acetyl-3-hydroxyphenoxy pentane A mixture of 5.1parts of 2,6-dihydroxyacetophenone, 7.7 parts of 1,5-di-bromopentane,and 2.3 parts of anhydrous potassium carbonate in 100 parts (by volume)of anhydrous acetone was refluxed for hrs. An examination of thismixture by thin layer chromatography showed unchanged 2,6-dihydroxyacetophenone, 1,5-bis(2-acetyl- 3-hydroxyphenoxy)pentane and suspected2-(5-bromo- :pentyloxy)-6-hydroxyacetophenone to be present. The acetonesolution was concentrated to half its volume and the residue was removedby filtration. After washing with water this residue yielded 1.9 partsof 1,5-bis(2-acety1-3- hydroxyphenoxy)pentane. The filtrate was taken todryness and chromatographed on an alumina column using ether as eluent.The 2-(5-bromopentyloxy')-6-hydroxyacetophenone came off in the firstfractions, as confirmed by thin layer chromatography. Evaporation ofthese collected fractions yielded 5 parts as an oil which was used asfollows without further purification. Thus a mixture of 2.4 parts of thecrude oil, 1.2 parts of resacetophenone, 1 part of anhydrous potassiumcarbonate and 40 parts (by volume) of dry acetone was refluxed for 20hrs. After cooling the acetone solution was filtered and evaporated todryness. The residue was crystallised from methanolwater to yield 1.85parts of1-(2-acetyl-3-hydroxyphenoxy)-5-(4-acety1-3-hydroxyphenoxy)pentanemelting between 91 and 91.5 C.

Analysis.C H O requires: C, 67.7%; H, 6.5%. Found: C, 67.3%; H. 6.7%.

( b) 1- 2-ethoxycarb onylchromon-S -yloxy) -5-Z-ethoxycarbonylchromon-7-yloxy pentane Analysis.C H O requires: C,64.9%; H. 5.3%.

Found: C, 64.1%; H, 5.3%.

( c) 1- Z-carboxychromon-S-yloxy) -5- 2-carboxychromon-7-yloxy pentaneTo 1.0012 parts of the above bis-ester in 30 parts (by volume) ofmethanol was added an amount of 0.969 N sodium hydroxide in methanoljust sufficient for the ester hydrolysis. This mixture was then heatedon the steambath for /2 hr., the solvent was distilled off and theresidue was taken up in Water and filtered, the filtrate was thenacidified with dilute hydrochloric acid. The solid which separatedproved difficult to filter and was, therefore, separated from theliquors by centrifuging, washing twice with water and recentrifuging.The 1-(2-carboxychromon- 5 yloxy) 5 (2-carboxychromon-7-yloxy)pentane(0.25 part) was crystallised from ethanol and had a melting pointbetween 249 and 251 C. with preliminary softenlng.

Analysis.C H O H O requires: 4.45%. Found: C, 60.3%; H, 4.4%.

This acid was dissolved in an equivalent amount of sodium bicarbonatesolution and freeze-dried to obtain the disodium salt.

20 EXAMPLE 1s (a) 1,3-bis 2-acetyl-3 -hydroxy-5-methylphenoxy) -2-hydroxypropane To a solution of sodium ethoxide in ethanol (from 0.83part of sodium and 20 parts by volume of ethanol) was added a solutionof 12 parts of 2,6-dihydroxy-4-methylacetophenone and 3.34 parts ofepichlorohydrin in 10 parts (by volume) of ethanol. The resultingmixture was stirred and refluxed for 4 hrs.; after cooling250 parts ofwater were added and the soIid was isolated by filtration.Crystallisation of this solid from ethanol yielded 4.15 parts of 1,3-bis2-acetyl-3-hydroxy-5-methylphenoxy) -2-hydroxypropane melting between185 and 186 C.

Analysis.C H O requires: C, 64.9%; H, 6.2%.

Found: C, 64.1%; H, 6.3%.

(b) 1,3-bis (2-carb oxy-7-methylchromon-5-yloxy) -2- hydroxypropaneEXAMPLE 19 (a) 1,3-bis 2-acetyl-4-ethyl-3-hydroxyphenoxy) -2- hydroxyprop ane 2,6-dihydroxy-3-ethylacetophenone was condensed withepichlorohydrin by the method of Example 18(a) to yield 1,3 bis(2 acetyl4 ethyl 3 hydroxyphenoxy) 2- hydroxypropane melting between and 137 C.(from ethanol).

Analysis.-C H O requires: C, 66.3%; H, 6.8%. Found: C, 66.7%; H, 6.9%.

( b) 1,3-bis(2-carboxy-8-ethylchromon-5-yloxy)-2- hydroxypropane Theabove compound was condensed with diethyl oxalate as in Example 1(b) toobtain 1,3-bis(2-ethoxycarbonyl-8-ethylchromon-5-y1oxy -2-hydroxypropane melting between 159 and 161 C. (from ethanol).

This ester was hydrolysed as in Example 5(c) to obtain the acid as thedihydrate crystallising from ethanol and melting between 193 and 194 C.

Analysis.C H O .2H O requires: C, 57.85%; H, 5.0%. Found: C, 57.5%; H,4.9%.

The disodium salt was then prepared as in Example 5(c).

EXAMPLE 201-(Z-carboxychromon-S-yloxy)-3-(2-carboxy-8-ethylchromon-S-yloxy)-2-hydroxypropane2,6-dihydroxy-3-ethylacetophonone was condensed with2-(2,3-epoxypropoxy)-6-hydroxyacetophenone as in Example 16(b) to yield1-(2-acetyl-3hydroxyphenoxy)-3- (2 acetyl 4 ethyl 3 hydroxyphenoxy) 2hydroxypropane melting between 102 and 103 C., from aqueous ethanol.

Analysis.C I-I O requires: C, 64.9% H, 6.2%. Found: C, 64.8%; H, 6.3%.

This diketone was condensed with diethyl oxalate using the method ofExample 1(b) and 1-(2-eth0xycarbonylchromon 5 yloxy) 3 (2 ethoxycarbonyl8 ethylchromon-S-yloxy)-2-hydroxypropane was obtained, melting between166 and 166.5 C. from ethanol.

Analysis.C H O requires: C, 63.0%; H, 5.1%. Found: C, 62.6%; H, 4.95%.

EXAMPLE 21 1,5 -bis 2-carboxychromon-8-yloxy pentane2,3-dihydroxyacetophenone was condensed with 1,5-dibromopentane usingthe method of Example 1(a) to obtain1,5-bis(2-hydroxy-3-a0etylphenoxy)pentane, melting between 103.5 and104.5 C. (from ethanol).

Analysis.-C H O requires: C, 67.7%; H, 6.5%. Found: C, 67.7%; H, 6.9%.

This ketone was condensed with diethyl oxalate as in Example 1(b) toyield 1,5-bis(2-ethoxycarbonylchromon- 8-yloxy)pentane melting between128 and 130 (from ethanol).

Analysis.C H O requires: C, 64.9%; H, 5.3%. Found: C, 64.5%; H, 5.4%.

As in Example 5(0) this ester was hydrolysed to the acid monohydratemelting between 237 and 238 C. (from ethanol).

Analysis.-C H O .H O requires: 4.45%. Found: C, 59.9%; H, 4.3%.

This acid was then converted to the disodium salt as in Example 5(c).

EXAMPLE 22 1,5-bis( 2-carboxy-8-methylchromon-7-yloxy pentane2,4-dihydroxy-3-methylacetophenone was condensed with 1,5-dibromopentaneusing the method of Example 1(a) to yield1,5-bis(4-acetyl-3-hydr0xy-2-methylphenoxy)pentane melting between 116and 117 C. (from ethanol).

Analysis.- C H O requires: C, 69.0%; H, 7.05%. Found: C, 68.4%; H, 7.3%.

This product was condensed with diethyl oxalate as described in Example1(b) to yield, after crystallisation from dioxan plus ethanol1,5-bis(Z-ethoxycarbonyl-S- methylchromon-7-yloxy)pentane, meltingbetween 196 and 197 C.

Analysis.-C H O requires: C, 65.95%; H, 5.65%. Found: C, 65.7%; H,6.05%.

The ester was hydrolysed using the method as in Example 5(0) to obtainthe acid melting between 274 and 276 from dioxan.

Analysis.C H O requires: C, 63.8%; H, 4.8%. Found: C, 63.9%; H, 5.0%.

The disodium salt of this acid was prepared as in Example 5 EXAMPLE 231,3-bis (2-carboxy-8-methylchromon-7 yloxy) -2- hydroxypropane2,4-dihydroxy-3-methylacetophenone was condensed with epichlorohydrin bythe method of Example 18(a) and after crystallising from ethanol,1,3-bis(4-acetyl-3- hydroxy-Z-methylphenoxy)-2-hydroxypropane wasobtained melting between 151 and 153 C.

Analysis.C H O requires: C, 64.9%; H, 6.2%. Found: C, 64.5%; H, 6.25%.

This ketone was then condensed with diethyl oxalate as described inExample 1(b) to yield, 1,3-bis(2-ethoxycarbonyl 8 methylchromon 7 yloxy)2 hydroxypropane melting between 191 and 193 (from dioxan plus ethanol).

Analysis.C H O requires C, 63.0%; H, 5.1%. Found: C, 63.0%; H, 5.24%.

The above ester was hydrolysed as in Example (0) to give 1,3 bis(2carboxy 8 methylchromon 7 yloxy)- 2-hydroxypropane dihydrate meltingbetween 272 and 275 C.

22 AnalySis.-C- H O .2H O requires: C, H, 4.5%. Found: C, 56.7%; H,4.35%.

The disodium salt of the acid was prepared as in Example 5 (0).

EXAMPLE 24 '1,S-bis(Z-carboxychromon-S-yloxy)-3-methylpentane2,6-dihydroxyacetophenone was condensed with 1,5-dibromo-S-methylpentane by the method described in Example 1(a) to give1,5-bis(2-aceytl-3-hydroxphenoxy)-3-methylpentane melting between and124 C. (from ethanol).

Analysis.-C H O requires: C, 68.4%; H, 6.8%. Found: C, 68.8%; H, 6.9%.

The ketone was then condensed with diethyl oxalate as in Example 1(b) toyield after crystallisation from ethanol 1,5-bis(2ethoxycarbonylchromon-5-yloxy)-3- methylpentane melting between 128 and130 C.

Analysis.C H O requires: C, 65.4%; H, 5.5%. Found: C, 65.3%; H, 5.4%.

Hydrolysis of the above ester by the method described in Example 5(0)yielded after crystallisation from aqueous ethanol1,5-bis(2-carboxychromon-S-yloxy)-3-methylpentane mono'hydrate melitngbetween 215 and 217 C.

Analysis.C H O .H O requires: 4.7%. Found: C, 61.6%; H, 4.8%.

This acid was converted to its disodium salt by the method described inExample 5(0).

EXAMPLE 25 1,3-bis(2-carboxy-6-chlorochromon-7-yloxy)-2-hydroxy propane;disodium salt 2,4-dihydroxy 5 chloroacetophenone was condensed withepichlorohydrin using the method as described in Example 18(a) to yield,after crystallisation from n-propanel, 1,3-bis(4-acety1-2-0hloro-5-hydroxyphenoxy -2-hydroxpropane melting between 197and 199 C.

Analysis.C H Cl O- requires: C, 53.1%; H, 4.2%. Found: C, 52.6%; H,4.7%.

The ketone was condensed with diethyl oxalate as described in Example1(b) to yield after crystallisation from ethanol, 1,3-bis(2ethoxycarbonyl-6-chlorochromom-7- yloxy)-2-hydroxypropane meltingbetween 199 and 202 C.

Analysis.-C H Cl O requires: C, 54.6%; H, 3.7%. Found: C, 54.7%; H,3.6%.

This ester was hydrolysed using the method described in Example 1(0) andthe disodium salt of1,3-bis(2-carboxy-6-chlorochromon-7-yloxy)-2-hydroxypropane tetrahydratewas obtained from aqueous ethanol.

EXAMPLE 26 2,4-dihydroxy-5-chloroacetophenone was condensed with2-(2,3-epoxypropoxy)-6 hydroxyacetophenone as in Example 16(b) to give1-(2-acetyl-3-hydroxyphenoxy)- 3-(4-acetyl-2-0hloro-5hydroxyphenoxy)-2-hydroxypropane melting between 139 and 140 C.

This diketone was condensed with diethyl oxalate as described in Example1(b) to yield after crystallisation from ethanol1-(2-ethoxycarbonylchromon-5-yloxy)-3- (2 ethoxycarbonyl-6-chlorochromon7 yloxy)-2-hydroxypropane melting between 166 and 168 C.

Analysis.C H ClO requires: C, 58.0%; H, 4.1%. Found: C, 57.4%; H, 4.3%.

This ester was converted to the disodium salt using the method asdescribed in Example 1(0) to give from aqueous ethanol the disodium saltof 1-(2-carboxychromon- 5yloxy)-3-(Z-carboxy-6-chlorochromon-7-yloxy)-2-hydroxypropanetetrahydrate.

Analysis.-C H ClNa O .4H O requires: C, H, 3.4%. Found: C, 45.5%; H,2.9%.

23 EXAMPLE 27 1,5 -bis 2-carboxychromon-6-yloxy) pentaneQuinacetophenone was condensed with 1,5-dibromopentane using the methoddescribed in Example 1(a) to obtain1,5-bis(3-acetyl-4-hydroxyphenoxy)pentane melting between 107 and 109C., from ethanol.

Analysis.C H O requires: C, 67.7%; H, 6.5%. Found: C, 67.8%; H, 6.8%.

The diketone was condensed, using the method as in Example 1(b), withdiethyl oxalate to yield l,5-bis(2-ethyoxycarbonylchromon-6-yloxy)pentane.

AnaIysis.C H O requires: C, 64.9%; H, 53%. Found: C, 64.7%; H, 5.5%.

This ester was hydrolysed using the method described in Example (c) andyielded, after crystallisation from dioxan,1,5-bis(2-carboxychromon-6-yloxy)pentane melting between 275 and 277 C.

Analysis.C H O requires: C, 62.5%; H, 4.2%. Found: C, 62.6%; H, 4.5%.

This acid was converted to its disodium salt by the method described inExample 5 (c).

EXAMPLE 28 1,3-bis(2-carboxychrornon-7-yloxy)-2-hydroxypropaneResacetophenone was condensed with epichlorohydrin as in Example 18(a)to give 1,3-bis(4-acetyl-3-hydroxyphenoxy)-2 hydroxypropane meltingbetween 152 and 154 C. (from ethanol).

AnaZysis.--C H O requires: C, 63.3%; H, 5.6%. Found: C, 63.5%; H, 6.2%.

1,3-bis(4-acetyl-3-hydroxyphenoxy)-2-hydroxypropane was condensed withdiethyl oxalate using the method as described in Example 1(b) to obtain1,3-bis(2-ethoxycarbonylchromon-7-yloxy)-2-hydroxypropane meltingbetween 178 and 180 C (from aqueous dioxan).

Analysis.-C H O requires: C, 61.8%; H, 4.6%. Found: C, 62.2%; H, 4.5%.

The ester was hydrolysed as in Example 5(c) to yield, aftercrystallisation from dioxan-water,l,3-bis(2-carboxychromon-7-yloxy)-2-hydroxypropane monohydrate meltingbetween 155 and and 165 C.

Al1alysiS.-C H O -H O requires: C, 56.8%; H, 3.7%. Found: C, 56.8%; H,3.7%.

The disodium salt of this acid was prepared as in Example 5(c).

EXAMPLE 29 1,2-bis 2-carboxychromon-5-yloxymethyl) benzene1,2-bis(bromomethyl)benzene was condensed with 2,6-dihydroxyacetophenone as described in Example 1(a) to give, aftercrystallisation from ethanol, 1,2-bis(2-acetyl-3-hydroxy-phenoxymethyl)benzene melting between 148 and 153 C.

Analysis.C I-I O requires: C, 70.9%; H, 5.5%. Found: C, 70.5%; H, 5.4%.

The diketone was condensed with diethyl oxalate as in Example 1(b) toyield 1,2-bis(2-ethoxycarbonylchrom0n-5-yloxymethyl)benzene meltingbetween 204206 C.

Analysis.C H O requires: C, 67.4%; H, 4.6%. Found: C, 68.1%; H, 4.5%.

This ester was saponified using the method as described in Example 1(c)to obtain the disodium salt as the tetrahydrate.

Analysis.C H Na O 4H O requires: C, 53.3%; H, 3.8%. Found: C, 54.0%; H,3.3%.

EXAMPLE 30 1,3-bis (2-carboxychromon-6-yloxy) -2-hydroxypropaneQuinacetophenone was condensed with epichlorohydrin as described inExample 18(a) to obtain after crystallisation from aqueous methanol1,3-bis(3-acetyl-4-hydroxyphenoxy)-2-hydroxypropane melting between 127and 129 C.

Analysis.-C H O requires: C, 63.3%; H, 5.6%. Found: C, 62.6%; H, 5.7%.

This ketone was condensed as described in Example 1(b) with diethyloxalate to yield 1,3-bis(2-ethoxy carbonylchromon 6yloxy)-2-hydroxypropane melting between 187 and 189 C. (fromethanol-dioxan-water).

Analysis.-C H O requires: C, 61.8%; H, 4.6%. Found: C, 62.0%; H, 4.3%.

Hydrolysis of this ester using the method described in Example 17(c)gave 1,3-bis(2-carboxychromon-6- yloxy)-2-hydroxypropane dihydratemelting between 268 and 270 C. (from ethanol-dioxan-water).

Analysis.C H O -2H O requires: C, 54.7%; H, 3.9%. Found: C, 55.0%; H,3.3%.

The disodium salt of this acid was prepared as described in Example5(c).

EXAMPLE 31 Disodium salt of 1-(2-carboxychromon-5-yloxy)-3-(2-carboxychromon-6-yloxy) -2-hydroxypropane Quinacetophenone was condensedwith epichlorohydrin as described in Example 16(a) to yield, aftercrystallisation from petrol (B.P. 6080 C.), 5-(2,3-epoxypro-.poxy)-2-hydroxyacetophenone melting between 76 and 79 C.

Analysis.C H O requires: C, 63.45%; H, 5.8%. Found: C, 64.0%; H, 5.6%.

This epoxide was condensed with 2,6-dihydroxyacetophenone as in Example16(b) to yield 1-(2-acetyl-3-hydroxyphenoxy)-3-(3acetyl-4-hydroxyphenoxy) 2 hydroxypropane melting between 185 and 186C., after crystallisation from ethanol.

Analysis.-C H O requires: C, 63.3%; H, 5.6%. Found: C, 63.5%; H, 5.6%.

This compound was condensed with diethyl oxalate as in Example 1(b) andafter crystallisation from ethanol, 1-(2-ethoxycarbonylchromon 5yloxy)-3-(2-ethoxycarbonylchromon-6-yloxy)-2-hydroxypropane was obtainedmelting between 164 and 166 C.

Analysis.C H O requires: C, 61.8%; H, 4.6%. Found: C, 62.4%; H, 4.5%.

This ester was hydrolysed to the disodium salt using the methoddescribed in Example 1(c) EXAMPLE 32 Disodium salt of1-(2-carboxychr0mon-5-yloxy)-3-(2-carboxychromon 8 -yloxy-2-hydroxypropane 2-(2,3-epoxypr0p0xy)-6-hydroxyacetophenone wascondensed with 2,3-dihydroxyacetophenone by the method described inExample 16(b) to give, after crystallisation from ethanol plus dioxan,1-(2-acetyl-3-hydroxyphenoxy)-3-3(3-acetyl 2hydroxyphenoxy)-2-hydroxypropane melting between 166 and 169 C.

Analysis.-C H O requires: C, 63.3%; H, 5 .6%. Found: C, 63.6%; H, 5.7%.

After condensation with diethyl oxalate, as in Example 1('b), thiscompound gave 1-(2 ethoxycarbonylchromon 5 yloxy) 3 (2ethoxycarbonylchromon-8- yloxy)-2-hydroxypropane melting between 162 andC., (from ethanol).

Analysis.C H O requires: C, 61.8%; H, 4.6%. Found: C, 61.6%; H, 4.75%.

This ester was saponified as described in Example 1(c) and the disodiumsalt was obtained.

EXAMPLE 33 1,8-bis (2-carboxychromon-5-yloxy) octane2,G-dihydroxyacetophenone was condensed with 1,8-dibromooctane as inExample 1(a) to give 1,8-bis(2-acetyl- 3-hydroxyphenoxy)octane meltingbetween 107 and 109 C., from benzene.

Analysis.C H O requires: C, 69.5%; H, 7.3%. Found: C, 69.6%; H, 7.25%.

This diketone was reacted with diethyl oxalate in the usual manner(Example 1(b)) to obtain after crystal- 25 lisation from ethanol,1,8-bis(Z-ethoxycarbonylchromon- -yloxy)octane melting between 139 and141 C.

Analysis.-C H O requires: C, 66.4%; H, 5.9%. Found: C, 66.0% H, 6.0%.

Hydrolysis of this ester as in Example 5 (c) yielded 1,8-bis(Z-carboxychromon-S-yloxy)octane monohydrate of indefinite meltingpoint.

Analysis.C H O .H O requires: C, 62.2%; H, 5.2%. Found: C, 61.1%; H,5.4%.

The disodium salt of this compound was prepared as in Example 5(c).

EXAMPLE 34 1,9-bis (Z-carboxychromon-S-yloxy nonane2,6-dihydroxyacetophenone was condensed with 1,9- dibromononane as inExample 1(a) to yield 1,9-bis(2- acetyl-3-hydroxyphenoxy)nonane meltingbetween 55- 59 C. after crystallising from ethanol.

Analysis.C H O requires: C, 70.1% H, 7.5%. Found: C, 69.7%; H, 7.5%.

This diketone with diethyl oxalate gave, using the method of Example1(b), 1,9 bis( 2 ethoxycarbonylchromon-5-yloxy)nonane crystallising fromethanol and melting between 128 and 129 C.

Analysis.-C H O requires: C, 66.9%; H, 6.1%. Found: C, 66.4%; H, 6.2%.

Hydrolysis of this ester as in Example 5 (c) yielded 1,9-bis(2-carboxychrornon 5 yloxy)nonane, crystallising from dioxan pluspetrol ether (B.P. 60-80% melting between 123 and 127 C.

Analysis.C H O requires: C, 64.9%; H, 5.3%. Found: C, 64.5%; H, 5.7%.

The disodium salt of this acid was prepared as in Example 5( c).

EXAMPLE 1,2-bis (2-carboxychromon-5-yloxy)ethane2,6-dihydroxyacetophenone was condensed with 1,2- dibromoethane usingthe method of Example 1(a) to obtain1,2-bis(2-acetyl-3-hydroxyphenoxy)ethane melting between 188 and 189after crystallisation from acetic acid.

Analysis.C H O requires: C, 65.4%; H, 5.5%. Found: C, 65.7%; H, 5.4%.

The condensation of this compound with diethyl oxalate was carried outas in Example 1(b) to yield after crystallisation from dioxan 1,2 bis( 2ethoxycarbonylchromon-5-yloxy)ethane melting between 264 and 265 C.

Analysis.C H O requires: C, 63.15%; H, 4.5%. Found: C, 63.0%;H, 4.7%.

This ester was hydrolysed using the method as in Example 17(c) to give1,2-bis(Z-carboxychromon-S-yloxy) ethane melting between 262 and 263 C.

Analysis. C H O requires: C, 60.3%; H, 3.2%. Found: C, 59.6%;H, 3.1%.

The disodium salt of this acid was prepared in the manner described inExample 5 (c).

EXAMPLE 36 1,3-bis(2-carboxychromon-5-yloxy)-2-chlorornethyl-2-hydroxymethylpropane; dipotassium salt tetrahydrate2,6-dihydroxyacetophenone was condensed with 3,3-bis(chloromethyl)oxetane using the method as described in Example 1(a)to give 3,3-bis(2-acetyl-3-hydroxyphenoxymethyl)oxetane melting between209 and 211 C.

Analysis.C H O requires: C, 65.3%; H, 5.7%. Found: C, 65.3%;H, 5.5%.

This oxetane (7 parts), 2 parts (by volume) of concentrated hydrochloricacid, 10 parts of water and 25 parts (by volume) of dioxan were heatedunder reflux together for 2 hrs. After filtering aqueous sodiumcarbonate was added until neutral and the yellow oil that precipitatedcrystallised on keeping. After recrystallising from ethanol 5.44 partsof1,3-bis(2-acetyl-3-hydroxyphenoxy)-2-chloromethyl-2-hydroxymethylpropanewere obtained melting between 148 and 150 C.

Analysis.-C H ClO requires: C, 59.6%; H, 5.4%. Found: C, 59.6%; H, 5.5%.r

This ketone was condensed with diethyl oxalate as in Example 1(b) toyield, after crystallising from ethyl acetate plus petrol ether (B.P.4060), l,3-bis(2-ethoxycarbonylchromon-S-yloxy) 2-chloromethyl 2hydroxymethylpropane melting between 165 and 168 C.

Analysis.C H ClO requires: C, 59.3%; H, 4.6%. Found: C, 59.0%; H, 4.7%.

To 0.8 part of the ester in 30 parts (by volume) of methanol was added3.15 parts of a 0.87 N solution of potassium hydroxide in methanol. Thissolution was heated under reflux for 10 minutes, d ecolourised withcharcoal, filtered and reduced in volume by evaporation until on cooling0.6 part of the dipotassium salt of 1,3- bis(2-carboxychromon-5-yloxy) 2chloromethyl-Z-hydroxymethylpropane tetrahydrate crystallised.

Analysis.-C I-I ClK O .4H O requires: C, 44.3%; H, 3.9%. Found: C,44.4%; H, 3.4%.

EXAMPLE 37 Disodium salt of l,3-bis(2-carboxychro mon-S-yloxy)-2eth0xypropane 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane,diethyl ester, 15 parts, was suspended in parts of ethyl iodide and 10parts of freshly prepared silver oxide was added with stirring. Thestirred suspension was heated under reflux for four days. The solidswere then filtered, washed with cold ethanol and then extracted withboiling ethanol in a Soxhlet extractor to obtain 9.7 parts of a mixtureof starting material with the required ethyl ether. This was separatedby chromatography on a silica gel column using chloroform as eluent, toobtain 20% by weight of the pure diethyl ester of 1,3-bis(2-carboxychromon-5-yloxy)-2-ethoxypropane melting between 192 and 193 C.

Analysis.C H O requires: C, 63.0%; H, 5.07%. Found: C, 63.1; H, 5.06%.

By the method of Example 1(c) this ester was converted to the disodiumsalt.

Analysis.C H Na O .2H O requires: C, H, 3.85%. Found: C, 52.2%; H,3.32%.

EXAMPLE 38 Disodium salt of 1,3-bis(2-carboxychromon-5-yloxy)-2-oxopropane A mixture of 4 parts diethyl ester of1,.3-bis(2-carboxychromon-S-yloxy)-2-hydroxypropane, 16 parts aceticanhydride and 24 parts dimethyl sulphoxide was ground in a revolvingglass jar containing glass beads for three days. The mixture was thenheated to C. for two hours and filtered while still warm. The solid waswashed with ethanol and recrystallised from a mixture of chloroform andpetrol to obtain 1.2 parts of the diethyl ester of 1,3-bis(Z-carboxychromon-S-yloxy)-2-oxopropane melting at 210 C.

Analysis.C H O requires: C, 62.1%; H, 4.21%. Found: C, 61.6%; H, 4.61%.

By the method of Example 1(c) part of this ester was converted to thesodium salt.

Analysis.C H Na O 4.H O requires: C, 47.4%; H, 3.43%; Na, 7.9%. Found:C, 48.1%; H, 2.80%; Na, 7.85%.

EXAMPLE 39 (a) 2,5-bis(2-acetyl-3-hydroxyphenoxymethyl) dioxan To asolution of 12.4 parts of 2,6-dihydroxyacetophenone in 50 parts ofisopropanol under nitrogen was added a concentrated solution of 5.4parts of potassium hydroxide in water. Benzene was added and the mixturedistilled to remove Water as an azeotrope. A solution of 15 parts of2,5-bis iodomethyl-dioxan in 50 parts of isopropanol was added and themixture heated with stirring under reflux for three days. The solventwas distilled off and water added. The mixture was extracted withchloroform which was then evaporated to leave a red oil. This wasextracted with boiling ether to leave 1 part of 2,5-bis(2-acetyl-3-hydroxyphenoxy methyl)-dioxan as an orange solid meltingbetween 230 and 232 C.

Analysis.-C H O requires: C, 63.5%; H, 5.77%. Found: C, 63.7%;H, 5.89%.

(b) Diethyl ester of 2,5-bis(2-carboxychromon-5-yloxymethyl) -dioxan Asin Example 1(b) 1 part of 2,5bis(2-acetyl-3-hydroxyphenoxy methyl)dioxanwas reacted with diethyl oxalate as far as the isolation of the sodiumsalt of the diketo ester. This was suspended in water and acidified withacetic acid to obtain an orange solid melting between 176 and 177 C.This was recrystallised from a mixture of ethanol and benzene to obtaina first crop of 0.3 part solid melting between 192 and 194 C. and whichthen solidified and remelted between 274 and 278 C. Analytical data andinfra-red spectra suggest this product to be the diethyl ester of1,6-bis(2-carboxychromon-S-yloxy)-2-hydroxy-5-hydroxymethyl 4 oxahexaneproduced by ring opening of the dioxan ring. A second crop of a solidmelting between 276 and 280 C. was obtained by concentrating thefiltrate. This was purified by recrystallisation from ethanol to obtain0.2 part of the diethyl ester of2,5-bis(2-carboxychromon-5-yloxymethyl)dioxan melting at 285 C. withdecomposition.

Analysis.C H O requires: C, 62.1%; H, 4.83%. Found: C, 62.3%; H, 4.61%.

EXAMPLE 40 1,5-bis- Z-carboxychromon-S-yloxy) -pentane A mixture of 37parts of 1,5-bis(2-acetyl-3-hydroxyphenoxy) pentane and 52 parts byweight of ethyl ethoxydichloroacetate (80% purity) was heated at 150-170for hours. After evaporating under reduced pressure the mixture thusobtained, which contained the diethyl ester of the desired acid, wasdissolved in acetic acid containing 17% concentrated hydrochloric acid.This solution was boiled under reflux for 4 hours. After cooling thesolid was filtered off, washed with water and crystallised from ethanolto yield 1,5-bis(2-carboxychromon-5- yloxy)pentane monohydrate meltingbetween 226 and 228 and shown to be identical with the material preparedin Example 6.

EXAMPLE 41 1,5-bis (2-carboxychromon-5-yloxy pentane To a mixture ofparts of l,5-bis(2-acetyl-3-hydroxyphenoxy)pentane and 20 parts ofpyridine cooled in ice was slowly added 13 parts of ethyloxalylchloride. The mixture was then allowed to stand for 24 hours andthen heated at 100 for minutes. After cooling, and pouring onto amixture of ice and excess of concentrated hydrochloric acid an oil wasformed which was extracted with chloroform, washed, and the chloroformsolution was dried over sodium sulphate. After filtration and removal ofthe solvent the residue was crystallised from ethanol to give thediethyl ester of 1,5-bis(2-carboxychromon-5-yloxy)pentane meltingbetween 150 and 152 and shown to be identical with a sample as preparedin Example 6.

EXAMPLE 42 (a) 1,5-bis(2-methylchromon-5-yloxy)pentane A mixture of 4.6parts of powdered sodium 7.44 parts of 1,S-bis(2acetyl-3-hydroxyphenoxy)pentane and 150 parts of ethyl acetate washeated under reflux for 2% hours with stirring.

The resulting orange solution was cooled and diluted with 400 parts ofether. The precipitated solid was extracted with water and the extractwas acidified with dilute hydrochloric acid. The precipitated oil wasextracted with chloroform and the chloroform solution was dried overanhydrous sodium sulphate, filtered, and the solvent was then removed toyield a red oil.

This oil was heated under reflux with ethanol and 0.5 part ofconcentrated hydrochloric acid for 10 minutes. The solution wasevaporated to leave an oil which was triturated with ether and theresulting solid was collected. This solid was crystallised from amixture of ethyl acetate and petroleum ether (B.P. 4060 C.) to give 4.82parts of 1,5-bis(Z-methylchromon-S-yloxy)pentane, melting point 140-3 C.The ether wash afforded a further 0.4 part of the same material.

Analysis.C H O requires: C, 71.41%; H, 5.75%. Found: C, 71.00%; H,5.87%.

(b) 1,5-bis 2-carb0xychromon-5-yloxy pentane To a mixture of 5 parts of1,5-bis(2-methylchromon-5- yloxy)pentane in parts of dioxan was added 6parts of finely divided selenium dioxide and the mixture was heatedunder reflux for 6 hours. After cooling, the precipitated selenium wasfiltered off and the solvent was removed from the filtrate under vacuum.The residue was dissolved in chloroform and the chloroform was extractedwith sodium bicarbonate solution. The crude product was precipitatedupon addition of hydrochloric acid to the alkaline extract and it wascrystallised from ethanol to yield1,5-bis(2-carboxychromon-5-yloxy)pentane as the monohydrate meltingbetween 226 and 228, identical with the material prepared in Example 6.

EXAMPLE 43 (a) 1,5-bis(Z-styrylchromon-S-yloxy)pentane A solution ofsodium ethoxide was prepared from 0.294 part of sodium and 8.0 parts ofethanol. To this was added with stirring over 10 minutes a mixture of1.5 parts of benzaldehyde and 2.7 parts of1,5-bis(2-methylchromon-5-yloxy)pcntane in 35 parts of ethanol. Themixture was stirred and heated under reflux for 4 hours and then allowedto stand to room temperature for 16 hours.

The brown oily solid which had precipitated was filtered 0E andtriturated with ether. The resulting solid was filtered otf anddissolved in glacial acetic acid, The solution was treated withcharcoal, filtered, and diluted with water to give 1.55 parts of1,5-bis(2-styrylchromon-5- yloxy)pentane, melting point 217220 C.

Analysis.C H O requires: C, 78.50%; H, 5.41%. Found: C, 77.4%; H, 5.87%.

(b) 1,5-bis 2-carboxychromon-5-yloxy pentane A solution of 10 parts ofpotassium permanganate in 200 parts of water was added to a solution of5 parts of 1,5-bis(2-styrylchromon-5-yloxy)pentane in 50 parts of purepyridine. The mixture was stirred at room temperature for several hours.The presence of excess of potassium permanganate was checked from timeto time and further amounts of a 5% aqueous solution of potassiumpermanganate were added as required. When no further oxidation tookplace the solution was acidified with hydrochloric acid and sulphurdioxide was passed to decolourise. The precipitated material wasfiltered off, washed with hot water and extracted with sodiumbicarbonate solution. On acidification the product was precipitated andwas filtered off, dried, and crystallised from ethanol to yield 1,5bis(2-carboxychromon-5-yloxy)pentane monohydrate melting between 226 and228 and shown to be identical with the material prepared in Example 6.

EXAMPLE 44 1,3-bis (Z-ethoxyc arbonylchromon-7-yloxy -2- hydroxypropaneA solution of sodium ethoxide was prepared from 0.115 part of sodium and30 parts of ethanol. To this 29 was added a mixture of 2.34 parts ofethyl-7-hydroxychromon-Z-carboxylate and 0.462 part of epichlorohydrin.The mixture was stirred and heated under reflux for 4 hours.

Half of the ethanol was evaporated off and the remaining mixture wasdiluted with 300 parts of water. The aqueous solution was then extractedwith chloroform. The organic solution was dried over anhydrous sodiumsulphate, filtered, and evaporated to leave a red oil. The yellow solidobtained by trituration of this oil with ethanol was filtered ofl andwashed with alcohol giving 0.12 part of 1,3-bis(2-cthoxycarbonylchromon7 yloxy)-2- hydroxypropane, melting point 178-9 C. The identity of theproduct with a sample as prepared in Example 28 was confirmed by amixed-melting point determination, by thin layer chromatography, and byinfra-red analysis.

EXAMPLE 45 1,5 -bis (2-carboxychromon-6-yloxy pentane A solution of 5.7parts of 1,5-dibromopentane in 80 parts of ethanol was added to asolution of 5.6 parts of potassium hydroxide and 33 parts ofhydroquinone in 40 parts of ethanol. The mixture was heated under refluxfor 16 hours, then the ethanol was evaporated off and the mixture wasdiluted with 200 parts of water, acidified with concentratedhydrochloric acid and the resulting precipitate was filtered off. Thesolid thus obtained was extracted with hot benzene and the solution wastreated with charcoal and filtered whilst hot. The solution on cooling,yielded 4.9 parts of 1,5-bis(4-hydroxyphenoxy) pentane melting point110-12.

Analysis.C H O requires: C, 70.8%; H, 6.99%. Found: S, 71.7%; H, 7.14%.

5.8 parts of 1,5-bis(4-hydroxyphenoxy)pentane were treated with asolution of 1.6 parts of sodium hydroxide in 10 parts of water. Waterwas evaporated from the mixture and the solid was dried in an oven at100. The solid was treated with 50 parts of dioxan and the mixture wasstirred and heated under reflux. Subsequently, 6.8 parts of diethylacetylenedicarboxylate were added dropwise to the mixture, which wasstirred and heated under reflux for 50 minutes. The mixture was cooledand acidified with 20% v./v. sulphuric acid, then the mixture wastreated with 25 parts of 25% sodium hydroxide solution and heated underreflux for 50 minutes. The mixture Was cooled, acidified with 20% v./v.sulphuric acid and dioxan was distilled 01f. The resulting precipitatewas filtered OE and Was extracted with sodium bicarbonate solution. Theextract was acidified with dilute sulphuric acid and the resultingprecipitate was filtered E and dried in air to give 10.4 parts of alight coloured solid, which was crushed with 30 parts of concentratedsulphuric acid. The mixture was allowed to stand for 40 minutes and thenit was filtered through a plug of glass-wool. The filtrate was tippedonto 100 parts of ice and the resulting precipitate was filtered off,washed with water and crystallised from aqueous dioxan to give 1.5 partsof 1,5-bis(2-carboxychromon-6-yloxy)pentane melting point 270 1, shownto "be identical with the material prepared in Example 27.

EXAMPLE 46 The activity of the new bis chromonyl compounds has beenevaluated by the antigen inhalation test on human volunteers who sufferfrom specific allergic asthma. The degree of asthma provoked by theinhalation of an antigen to which the volunteers are sensitive can bemeasured by repeated estimation of the increase of air-way resistance.

A suitably designed spirometer was used to measure the forced expiratoryvolume at one second (F.E.V. and hence the changes in the air wayresistance. The antiallergic activity of a compound is estimated fromthe difierence between the maximum percent F.E.V. reduction followingcontrol and test provocations after drug 30 administration conductedunder identical experimental conditions. Thus:

Percent protection: X

Av. max. percent F.E.V. Max. percent F.E.V. fall control shock fall testshock Av. max. percent F.E.V. fall control shock The compounds undertest were administered as an aerosol by inhalation for five minutes, twohours before challenge with antigen. The compounds for administrationwere dissolved in sterile water at a concentration of 0.5% andaerosolized from a Wright nebulizer operating at 10 litres/ minute airflow, giving a total weight of drug aerosolized of 5 mg. The followingtable shows the protection obtained with a number of the newbis-chromonyl compounds.

Compound under test Percent protection Disodium salt of1,5-bis(2-carboxychromon-fi-yloxy)- pentane 30-35 Disodium salt of1,7-bis(2-carb0xychro 0x 2,6-dihydroxy-4-oxaheptane 25-30 Disodium saltof 1,4-bis(2-carboxychr0m0n-5-yloxy) butane 45-50 Disodium salt ofl,4-bis(2-carboxychromon-5-y10xy)- 2,3-dihydroxy-butane 40-45 Disodiumsalt of 1,4-bis(Z-carboxychromon-5-yloxy)-2- hydroxy-butane 50-55Disodium salt of 1,4-bis(2carboxychromon5-yloxy)- but 2 arm. 45-50 ,10carboxyehromonhydl'oxypropane 05-70 Disodiurn salt of1,3-bis(Z-carboxyehromon-5-yloxy)- p ropane 40-45 Disodium salt of1,5-bis(2-carb0xy-8-chloro-clu'omon-5- yloxy) pentane 20-25 Disodiumsalt of 1,5-bis(2-carboxychromon-G-yloxy)- pentane 45-50 Disodium saltof 1,3-bist2-carboxychromon Z-hydroxypropano 40-45 Disodium salt of1,3-bis(2-carboxy-8-ethyl-chromon-5- I yloxy) -2-hy lroxyprop ane 20-25Disodium salt of 1,2-bis(Z-carboxycln'omon-5-yloxymethyl)- benzene 30-35Disodium salt of 1-(Z-carboxychromon-S-yloxy)-3-(2-carboxychromon-7-yloxy)-2hydroxypropanc 45-50 Disodium salt of1,3-bis(Z-carboxychromon-ti-yloxy)- 2-hydroxypropane. .W. 40-45 Disodiumsalt of 1,3-bis(2-carbo methylchromon- 7-yloxy) -2-hy droxypropane 15-20Disodium salt of l-(2-earboxychromon-5-yloxy)-3-(2-carboxy-B-ethyl-chromon-5-yloxy)-2-hydroxy-prop anc. 25-30 Dipotassiumsalt of 1,3-bis(2-carboxychromon-5-yl0xy)-2-chloromethyl-z-hydroxymethylpropane 40-45 Disodium salt ofl,5-bis(2-carboxychromon-5-yloxy)- 3-methylpentane 20-25 Disodium saltof 1-(2-carb0xychromon-5-yloxy)-3-(2- earl) oxy-6chloro-chrom0n-7-yloxy)-2-hydroxypropane 35-40 Disodium salt of1,3-bis(2-carboxychromon-5-yloxy)- acetone 30-35 Disodium salt of1,3-bis(2-cal'boxy Z-ethoxyprop ane 30-35 Clinical investigations of1,3-bis(2-carboxychromon-5- yloxy)-2-hydroxypropane in the form of itsdisodium salt, hereinafter referred to as compound A, have been carriedout on volunteers having clinical evidence of allergic asthma. In thecase of some of the volunteers this asthma was identified as extrinsicasthma, i.e. was provoked by a specific antigen; the majority of thevolunteers, however, were classified as sulfering from intrinsic asthma,i.e. did not respond to a large number of skin and aerosol provocationtests.

In the case of the volunteers suffering from extrinsic asthma it waspossible to assess the degree of protection aiforded quantitativelyusing the test procedure described above.

In the case of subjects suflFering from intrinsic asthma the therapeuticefiFect of compound A could be assessed subjectively and by objectivetests of lung function.

The results of the clinical investigations may be summarised as follows:

(1) Inhalation of Compound A in doses of 1-20 mg. repeated at 4 to 8hour intervals is well tolerated; no side effects or other evidence oftoxicity being observed during a continuous trial period of months.

(2) The therapeutic effect of compound A maybe apparent in 4 hours butincreases for several days with continued therapy, reaching a maximum in1 to 2 weeks. A dose of 2-6 mg. 4 to 6 hourly induces a significantimprovement as shown by objective tests of lung function in mild cases.

In more severe cases, doses of up to 20 mg. at 4 to 6 hourly intervalsare required to produce a significant improvement.

In quantitative objective tests it has been found that compound A,administered in a dose of 20 mg. gives up to 84% protection 2 hoursafter administration, up to 70% protection 4 hours after administration,and noticeable protection, e.g. about 20% protection 18 hours afteradministration.

Subjective improvement usually includes:

(a) Reduction of chest tightness;

(b) Increased tolerance to exercise; and

(c) Reduced sputum volume and cough.

Withdrawal of therapy with compound A was followed by a relapse within48 hours in severe cases or after 7-14 days in mild cases.

The acute I.V. toxicity of Compound A, in rats, has been found to below; i.e. the LD is at least 1000 mg./kg.

We claim:

1. A member selected from the group consisting of a bis-chromonylcompound of the formula and therapeutically acceptable salts, esters andamides thereof, in which R R R R R and R are each selected from thegroup consisting of hydrogen, halogen, hydroxy, lower alkyl, loweral'koxy, hydroxyloweralkyl, haloloweralkyl, hydroxyloweralkoxy,loweral-koxyloweralkoxy and carboxyloweral-koxy; and X is selected fromthe group consisting of saturated and unsaturated, straight and branchedhydrocarbon chains which may be interrupted by a member selected fromthe group consisting of benzene rings, dioxanyl, oxygen atoms andcarbonyl groups, and which may be substituted by a member selected fromthe group consisting of halogen atoms, hydroxy groups and lower alkoxygroups.

2. A compound according to claim 1 wherein the hydrocarbon chain of thegroup X has from 3 to 7 carbon atoms.

3- A compound according to claim 1 wherein the group X is substituted byan hydroxyl group.

4. A compound according to claim 1 wherein X is a 2-hydroXy-trimethylenegroup.

5. A compound according to claim 1 in the form of an ammonium salt.

6. A compound according to claim 1 in the form of an alkali metal salt.

7. A compound according to claim 1 in the form of an alkaline earthmetal salt.

8. A compound according to claim 1 in the form of an amine salt.

9. A compound according to claim 1 in the form of an ester.

10- A compound according to claim 1 in the form of an amide.

11. A bis-chromonyl compound according to claim 1 wherein each of R R Rand R is hydrogen.

12. A compound according to claim 11 wherein the hydrocarbon chain ofthe group X has from 3 to 7 carbon atoms.

13. A compound according to claim 11 wherein the group X is substitutedby an hydroxyl group.

14. A compound according to claim 11 wherein X is a2-hydroxytrimethylene group.

15. A compound according to claim 11 in the form of an ammonium salt.

16. A compound according to claim 11 in the form of an alkali metalsalt.

17. A compound according to claim 11 in the form of an alkalinc earthmetal salt.

18. A compound according to claim 11 in the form of an amine salt.

19. A compound according to claim 11 in the form of an ester.

20- A compound according to claim 11 in the form of an amide.

2?. A compound according to claim 1 in which each of R R R R, R and R ishydrogen.

.-.3. A compound according to claim 21 wherein the hydrocarbon chain ofthe group X has from 3 to 7 carbon atoms.

23. A compound according to claim 21 wherein the group X is substitutedby an hydroxyl group.

24- A compound according to claim 21 wherein X is aZ-hydroxytrimethylene group.

25. A compound according to claim 21 in the form of an ammonium salt.

26. A compound according to claim 21 in the form of an alkali metalsalt.

27. A compound according to claim 21 in the form of an alkaline earthmetal salt.

28. A compound according to claim 21 in the form of an amine salt.

' 29. A compound according to claim 21 in the form of an ester.

30. A compound according to claim 21 in the form of an amide.

31. A compound according to claim 1 being 1,3-bis(2-carboxychromon-S-yloxy)-2-hydroxypropane of the formula:

I Am

or a therapeutically acceptable ammonium, alkali metal, alkaline earthmetal or amine salt thereof.

32. A bis-chromonyl compound selected from:

1,5-bis 2-carb oxychromon-S-yloxy -pentane;

1,4-bis 2-carboxychromon-5-yloxy butane;

1,4-bis 2-carboxychromon-5-yloxy -2,3-dihydr0xybutane;

1,4-bis'(Z-carboxychromon-S-yloxy -2-hydroxy-butane;

1,4-bis(Z-carboxychromon-S-yloxy -but-2-ene;

1,10-bis(2-carboxychromon-5-yloxy)-decane;

1,6-bis (2-carboXychromon-5-yloxy -hexane;

1,3-bis 2-carboxychromon-5-yloxy -2-hydroxypropane;

1,3-bis Z-carboxychromon-S-yloxy -propane;

1,5-bis 2-carboxychromon-6-yloxy -pentane;

1,5-bis 2-carboxychromon-7-yloxy) -pentane;

1,3-bis (2-carboxyohromon-7-yloxy -2-hydroxypropane;

1,2-bis (2-carboxychromon-S-yloxymethyl) benzene;

